Cholecystokinins (CCK) are neuropeptides (see, Mutt and Jorpes, Biochem. J., 125, 678 (1971)) which exist in both gastrointestinal tissue and the central nervous system (V. Mutt, Gastrointestinal Hormones, G. B. J. Glass, ed., Raven Press, N.Y., 1980, p. 169), and include, e.g., CCK-33, a neuropeptide of thirty-three amino acids and its carboxyl terminal octapeptide, CCK-8. These molecules are believed to be physiological satiety hormones and, therefore, may play an important role in appetite regulation (G. P. Smith, Eating and Its Disorders, A. J. Stunkard and E. Stellar, Eds., Raven Press, New York, 1984, p. 67).
In addition, CCK's stimulate colonic motility, gall bladder contraction, and pancreatic enzyme secretion, and inhibit gastric emptying. CCK's reportedly also co-exist with dopamine in certain mid-brain neurons, and thus may additionally play a role in the functioning of dopaminergic systems in the brain, as well as serve as neurotransmitters in their own right. See: A. J. Prange et al., "Peptides in the Central Nervous System", Ann. Repts. Med. Chem., 17, 31, 33 (1982), and references cited therein; J. A. Williams, Biomed. Res., 3, 107 (1982); and J. E. Morley, Life Sci., 30, 479 (1982).
Antagonists to CCK have been useful for preventing or treating CCK-related disorders of the gastrointestinal, central nervous and appetite-regulatory systems of mammals, especially of humans. Three distinct chemical classes of CCK-receptor antagonists have been reported. The first class comprises derivatives of cyclic nucleotides, of which dibutyryl cyclic GMP has been shown to be the most potent by detailed structure-function studies (see, N. Barlos et al., Am. J. Physiol., 242, G161 (1982) and P. Robberecht et al., Mol. Pharmacol., 17, 268 (1980)). The second class comprises peptide antagonists which are C-terminal fragments and analogs of CCK, of which both shorter (Boc--Met--Asp--Phe--NH.sub.2, Met--Asp--Phe--NH.sub.2) and longer (Cbz--Tyr(SO.sub.3 H)--Met--Gly--Trp--Met--Asp--NH.sub.2) C-terminal fragments of CCK can function as CCK-antagonists, according to recent structure-function studies (see, R. T. Jensen et al., Biochim. Biophys. Acta., 757, 250 (1983), and M. Spanarkel et al., J. Biol. Chem., 258, 6746 (1983)). Then, the third class of CCK receptor antagonists comprises the amino acid derivatives: proglumide, a derivative of glutaramic acid, and the N-acyl tryptophans, including para-chlorobenzoyl-L-tryptophan (benzotript), (see, W. F. Hahne et al., Proc. Natl. Acad. Sci. U.S.A., 78, 6304 (1981) and R. T. Jensen et al., Biochim. Biophys. Acta., 761, 269 (1983)). All of these compounds, however, are relatively weak antagonists of CCK (IC.sub.50 : generally 10.sup.-4 M, but down to 10.sup.-6 M in the case of the peptides) and the peptide CCK-antagonists have substantial stability and absorption problems.
The compound, 7.beta.-((2,3,9,9A.alpha.-tetrahydro-9.alpha.-hydroxy-2-(2-methylpropyl)-3 -oxo-1H-imidazo-(1,2-A)-indol-9-yl)-methyl)quinazolino(3,2-A)(1,4)benzodiaz epin-5,13-(6H,7H)dione of the formula (I): ##STR1## which is produced in a controlled aerobic fermentation of a strain of Aspergillus alliaceus Thom and Church, preferably strain ATCC No. 20655 or strain ATCC No. 20656, as disclosed in U.S. application Ser. No. 509,883, filed Sept. 20, 1983 now U.S. Pat. No. 4,530,790 (which is incorporated herein by reference), has been shown to be a CCK-antagonist.
It was an object of this invention to identify substances which demonstrate improved potency versus the compound, 7.beta.-((2,3,9,9A.alpha.-tetrahydro-9.alpha.-hydroxy-2-(2-methylpropyl)-3 -oxo-1H-imidazo(1,2-A)indol-9-yl)-methyl)quinazolino(3,2-A)(1,4)benzodiazep in-5,13-(6H,7H)dione, in antagonizing the function of cholecystokinins in disease states in mammals, especially in humans. It was another object of this invention to develop a method of preparing these novel cholecystokinin-antagonists. It was also an object of this invention to develop a method of antagonizing the function of cholecystokinins in disease states in mammals. It was still a further object of this invention to develop an improved method of preventing or treating disorders of the gastrointestinal, central nervous and appetite regulatory systems of mammals, especially of humans.